Clinical studies suggest that males and females may differ in their motivation to use cocaine and show distinct patterns of relapse to cocaine abuse. Human female cocaine addicts report enhanced craving for cocaine during the follicular phase of the menstrual cycle, when plasma progesterone levels are low. In addition, women show increased motivation to return to cocaine use after stressful life periods. Consistent with the clinical evidence, recent preclinical studies have identified sex differences in the motivation to seek cocaine during cocaine self-administration, and during reinstatement of cocaine-seeking in an animal model of relapse. Specifically, females display increased responsivity to interoceptive cues, such as a challenge dose of cocaine, when compared to males. Moreover, this increased sensitivity to drug-seeking in females is closely linked to the estrous cycle, since the greatest degree of cocaine-seeking occurs during vaginal estrus, when plasma progesterone levels show an inverse relationship with cocaine-seeking. While sex and hormone dependent differences in drug-seeking exist, no studies have focused on sex differences and hormonal regulation of cocaine-taking and cocaine-seeking in response to stress, a well established clinical risk factor. Furthermore, it is yet to be determined whether stress-induced cocaine-seeking relates to ovarian hormones, or other related cycle-dependent factors. Therefore, the proposed dissertation studies aim to identify sex differences in stress-induced cocaine-seeking during cocaine self-administration and during relapse by stress-induced reinstatement of drug-seeking. Additionally, the interactions between estrous cycle phase, progesterone levels, and progesterone receptors in response to the pharmacological stressor yohimbine, will be investigated as they relate to enhanced cocaine-seeking. The findings obtained from these studies will be closely related with ongoing clinical research at MUSC on yohimbine-induced stress and cue reactivity in cocaine-dependent men and women, thus providing a unique translational approach to determine the relationships between sex differences in stress reactivity and their implications for gender specific treatment of cocaine dependence and relapse. for "Sex differences in the effects of stress on cocaine seeking " (R36) This project is aimed at understanding sex differences in the behavioral features and associated neuroadaptations involved in compulsive cocaine seeking as a response to stress using the an animal model of cocaine addiction and relapse. Information gained from this project will provide an understanding of the relationship between sex differences in stress reactivity and their implications for cocaine dependence and relapse. [unreadable] [unreadable] [unreadable]